Wednesday, October 17, 2018

3050. MDMA’s Potential for Treating PTSD

By Kevin Francotti, Slate, October 16, 2018

By the 1970s, the cultural zeitgeist around LSD was such that, despite nearly three decades of serious research touting the drug’s medical potential and its integral involvement in the discovery of serotonin’s function in the brain, further development was squashed under the full weight of an oppressive, authoritarian crackdown. Now, another drug that researchers started examining from a similar lens in the ’80s and ’90s may become a prescription medicine: MDMA. Known to the public as ecstasy (and more recently as molly), it has quietly been used in a clinical setting by a small community of therapists since the late ’70s (and is often still used in “underground treatment” settings). It has also been slowly gaining steam toward full-on medical approval: The Food and Drug Administration, as part of its assessment of whether MDMA warrants the agency’s approval, recently approved large-scale testing in humans. If it goes well, what has been a painstaking effort of nearly four decades of drug development research may soon culminate in MDMA being in therapy rooms as a legally available medicine for the treatment of post-traumatic stress disorder.

The question is whether we’re approaching this potentially game-changing expansion in the right way. It’s understandable that many proponents of MDMA therapy have grandiose expectations—the current treatment options for PTSD are largely inadequate. Just two medications are approved for PTSD and are meant to simply manage some of the symptoms, but they’ve been shown to be only somewhat effective at that. MDMA seems like a promising alternative: It has an unconventional history and novel therapeutic efficacy, with dramatic results from the initial clinical trials boasting an 83 percent reduction in symptoms among the majority of trial participants, and over two-thirds of participants no longer meeting DSM criteria for PTSD diagnosis following treatment. But significant questions about just how much of an impact this treatment could have might be a buzzkill to MDMA’s promise as a medicine.

In simple terms, PTSD develops in someone when one or more traumatic events are experienced, and the subsequent anxiety related to the trauma significantly interferes with quality of life, ability to hold a job, and interpersonal relationships. It’s a condition that is fundamentally resistant to treatment because often the necessary criteria for successful psychotherapy—such as trust in one’s therapist and empathy towards oneself—are often critically lacking in someone who’s been traumatized.

MDMA affects the brain almost as if it were specially designed to treat the symptoms that prevent someone with PTSD from succeeding in psychotherapy. Synapses are primarily flooded with serotonin, which provides a pleasant euphoria allowing someone to face their painful thoughts and feelings. At the same time, the release of dopamine, norepinephrine, oxytocin—sometimes referred to as the “empathy chemical”—cortisol, and prolactin reinforces the mood lift while attenuating anxiety and the fear response, acting in concert to amplify the therapeutic bond.

Of course, bringing a drug through the FDA approval process is no small task, let alone one currently listed in Schedule I of the Controlled Substance Act, the most restrictive class of drugs deemed to have no medical use and a high potential for abuse. Though no federal agency has funded a single study looking for potential benefits from MDMA, the government’s own efforts to corroborate some of the outlandish claims of its danger to users—including its potential to eat away at brain tissue—failed, and some of that same research was actually later used to convince the FDA that MDMA was safe enough to test in humans. Since 1986 (the same year the Drug Enforcement Administration permanently designated MDMA as a Schedule I substance), a small nonprofit known as the Multidisciplinary Association for Psychedelic Studies (MAPS) has been hoping to be the first to break such ground. In a handful of small-scale clinical trials, researchers showed that using MDMA in combination with psychotherapy can effectively treat people with PTSD. MAPS must now replicate the results on a larger scale involving hundreds of participants recruited by over a dozen research sites—a process known as phase 3.

The irony in pharmaceutical drug development is that the FDA doesn’t recommend prescription approval based on how an experimental drug works: It makes that assessment based simply on whether it’s more effective than placebo, and whether any side effects are tolerated reasonably well in the majority of people it’s studied in. The FDA functions merely as a regulatory agency that provides guidelines on how to conduct drug development research and approves experimental protocols but ultimately, when it comes to the science itself, that focus is left to the study’s sponsor—in this case, MAPS. MAPS is somewhat unique compared to other pharmaceutical companies because, in addition to their MDMA development efforts, they are also funding basic science research to show what mechanisms are involved in successful treatment.

This line of research remains preliminary, as most of the findings are from animal studies and only a few human participants (including MAPS Executive Director Rick Doblin). Results suggest MDMA’s facilitation of processes known as fear extinction and memory reconsolidation may be part of the therapy’s beneficial outcomes for people with PTSD. Based on the current evidence, if I were a careful scientist, I’d say that we don’t yet know whether MDMA therapy does actually work because it’s all still very preliminary, but it’s worth continued investigation.
The need for the treatment, however, is enormous and pressing. According to the National Institutes of Health, nearly 8 million American adults are affected by PTSD. Only around 100 people have participated in the first two phases of clinical development of MDMA-assisted psychotherapy for PTSD. This is not an unusually low number of people at this stage of experimental drug research, but the fact that it’s taken over a quarter-century to reach that number is. By comparison, the pharma giant Eli Lilly took only seven years to earn FDA approval for Prozac, the first in the class of antidepressants known as “selective serotonin reuptake inhibitors” (SSRIs).

The waiting list for participants hoping to enroll in the phase 3 trials is in the tens of thousands (most of the discretion around recruitment is left up to the teams at each of the individual research sites). Recruitment for clinical trials is challenging—the FDA’s guidelines are strict, so participants are often screened out for inability to come off contraindicated medication, past suicide attempts, personal or family history of psychosis, or failure to meet minimum scores on objective symptom measures. There are also logistical barriers, like being unable to afford to take time off work to make the appointments, securing child care, and travel costs. These requirements tend to result in socioeconomic bias in who makes the cut.

This issue isn’t trivial: A recently published review of the demographics from 18 studies involving psychedelics showed that a substantial majority of participants were non-Hispanic whites, and were not a demographically balanced socioeconomic representation of the geographic regions participants were recruited from. The authors of the review paper are attempting to directly address this inequity as part of a MAPS-sponsored MDMA therapy team studying treatment of racial trauma at the University of Connecticut. They are also consultants to ensure the phase 3 protocols are more sensitive to ethnocultural dynamics. (The National Institutes of Health mandate that NIH-funded research include diverse participant samples, but the FDA’s regulations do not require this, and MAPS receives no NIH funding.)

Last year, MAPS’ MDMA research was granted a “Breakthrough Therapy” designation that the FDA uses to streamline the regulatory process. Next year, MAPS is expecting to apply for another FDA program called “Expanded Access” wherein an unapproved drug can be given special exemptions allowing for use on a case-by-case basis (and not just for PTSD). This is promising but also likely to reinforce some of these structural problems—case-by-case exemptions are not likely to be covered by insurance. And it remains unclear how many people with PTSD will be able to access MDMA therapy even if it becomes medicine—there are some troubling indicators that it will stay limited. Insurance coverage remains an open question, and through Medicaid and Medicare are generally required to cover all FDA-approved drugs, private insurers have slightly more room to argue denials of coverage. If insurance does not cover it, it’s likely that the only people able to afford MDMA therapy will be the few privileged by a wealth of resources, able to pay out of pocket and commit to the time-intensive therapy that must accompany the medication in order for it to be effective.

As a nonprofit that’s also the sole owner of its own subsidiary, the MAPS Public Benefit Corporation, the company will not be allowed to advertise treatment if it is approved, according to statements made by Doblin. Instead, it will serve as a licensing body and training institution that will yield the only therapists permitted to administer MDMA therapy. That means those able to provide the therapy will likely be relying on a business model dependent on maximizing cash-ready patients seeking treatment. Venture capitalist–backed for-profit pharmaceutical companies are already becoming involved in similar areas of psychedelic medicine development. We’ve seen how aggressive marketing of opiate painkillers wrought havoc, and with the continuing practice of direct-to-consumer advertising, it doesn’t require too big an imagination to think of what might go wrong in that market.

As a cynical harbinger of the harms inherent in a capitalist society, particularly toward the already under-resourced, I fear MDMA’s arrival as a prescription medicine for PTSD will simply be as the most glowing product in the growing cottage industry for trauma treatment that only the rich and comfortable can access. I worry that we have no real plan of ensuring that it is available and accessible to the people that in many ways, need it the most. In this way, the story of prescription MDMA might mirror the unmet promises of the antidepressant boom, and that fate is just marginally better than if it went the way of LSD. When antidepressants first came to the market, we leapt on their easy potential and failed to address the factors driving depression rates, resulting in medications that are now barely as effective as placebo.

Even a seemingly powerful unique treatment like MDMA therapy won’t reach its potential if we don’t ensure that all people who need it can access it, along with the entire recommended process of care. Essentially, it’s never enough to just approve the treatment—you also have to assess the process. The FDA is tasked with assessing the efficacy. It’s unclear who’s tasked with assessing access. 

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